A retrovirus designated human immunodeficiency virus (HIV), particularly the strains known as HIV type-1 (HIV-1) virus and type-2 (HIV-2) virus, is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the insertion by virally-encoded integrase of +proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3′ termini of the linear proviral DNA; covalent joining of the recessed 3′ OH termini of the proviral DNA at a staggered cut made at the host target site. The fourth step in the process, repair synthesis of the resultant gap, may be accomplished by cellular enzymes.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)]. All three enzymes have been shown to be essential for the replication of HIV.
It is known that some antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, including reverse transcriptase inhibitors such as azidothymidine (AZT) and efavirenz and protease inhibitors such as indinavir and nelfinavir. The compounds of this invention are inhibitors of HIV integrase and inhibitors of HIV replication. The inhibition of integrase in vitro and HIV replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro in HIV infected cells. The particular advantage of the present invention is highly specific inhibition of HIV integrase and HIV replication.
The following references are of interest as background:
Tisler et al., Org. Prep. and Proc. Int. 1990, 22: pp. 532-534, discloses the preparation of methyl 3-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylate via the acid-catalyzed condensation of dimethyl diacetoxyfumarate with 2-aminopyridine. Methyl 3-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylate is also disclosed.
U.S. Pat. No. 6,921,759 (corresponding to WO 02/30930), U.S. Pat. No. 6,919,351 (corresponding to WO 02/30426), and U.S. Pat. No. 6,841,558 (corresponding to WO 02/55079) each disclose certain 8-hydroxy-1,6-naphthyridine-7-carboxamides as HIV integrase inhibitors.
WO 02/036734 discloses certain aza- and polyaza-naphthalenyl ketones to be HIV integrase inhibitors.
WO 02/06246 discloses certain 2-aryldihydroxypyrimidine-4-carboxylic acids that are useful as hepatitis C viral polymerase inhibitors. WO 03/062211 discloses certain pyrimidinone derivatives that are viral polymerase inhibitors, especially the polymerase enzyme of the hepatitis C virus.
US 2004/0229909 discloses certain compounds having integrase inhibitory activity.
WO 03/35076 discloses certain 5,6-dihydroxypyrimidine-4-carboxamides as HIV integrase inhibitors, and WO 03/35077 discloses certain N-substituted 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamides as HIV integrase inhibitors.
WO 03/062204 discloses certain hydroxynaphthyridinone carboxamides that are useful as HIV integrase inhibitors.
WO 04/004657 discloses certain hydroxypyrrole derivatives that are HIV integrase inhibitors.
WO 20004/058576 discloses certain tetrahydro-4H-pyrido[1,2-a]pyrimidines and related compounds that are useful as HIV integrase inhibitors.
WO 2005/016927 discloses certain nitrogenous condensed ring compounds that are HIV integrase inhibitors.